This proposal aims to examine the neurobiological mechanisms that subserve distinct forms of long-term memory, and to explore the relationship between them. Episodic memory refers to conscious memory for new events, and depends on the medial temporal lobe (MTL). Incremental stimulus-response learning refers to gradual learning of stimulus-response regularities over many trials, and is thought to depend on the basal ganglia (BG). While initial evidence has suggested that the neural substrates of these forms of memory operate as distinct and independent memory systems, recent data alternately suggest that the MTL and BG may jointly contribute to both forms of knowledge or that there may be a competitive interaction between these neural systems. Beyond MTL and BG, other data indicate that the acquisition and expression of both of these forms of memory are modulated by prefrontal cortex (PFC). The proposed research will address fundamental questions regarding the nature of MTL, BG, and PFC contributions to episodic and incremental learning, and the relationship between them. We will use fMRI to examine the temporal dynamics of activity within, and between, each system over the course of learning. We specifically aim to understand how the temporal profile of neural activity during learning relates to changes in memory performance (Expts 1-3). We will subsequently examine the nature of the relationship between the systems more directly, by determining how modulation of each system impacts activity and performance of the other. These fMRI studies will test whether functional coupling or competition exists between these systems, how such interactions change over time, and whether putative between-system interactions are direct or mediated (Expts 4-6). Finally, we will specifically examine the role of PFC in incremental and episodic learning, and in mediating putative between-system interactions during learning, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS). EEG will specify the temporal profile of PFC contributions to episodic and incremental learning (Expts 7-8), and the obtained fMRI and EEG data will guide TMS disruption of PFC function to test the necessity of PFC mechanisms for learning (Expts 9-10). Collectively, the proposed research will advance understanding of the temporal and spatial characteristics of MTL, BG, and PFC involvement in episodic and incremental learning, including whether and how interactions between these neural systems impact memory. The resulting knowledge will provide a foundation for understanding memory impairments in various neurological diseases and mental disorders that are associated with MTL, BG, and PFC dysfunction, including schizophrenia. Indeed, while not part of this proposal, we will draw directly on the outcomes from these studies to inform our investigations of memory deficits in schizophrenia (in collaboration with Dr. Carol Tamminga). [unreadable] [unreadable] [unreadable]